Minimization of Transplant Immunosuppression: An Elusive Goal

Minimization of Transplant Immunosuppression: An Elusive Goal



(Article introduction authored by Conquest Editorial Team)

Balancing immunosuppression in kidney transplant recipients (KTRs) is challenging. Standard triple-drug therapy (tacrolimus, mycophenolate mofetil, and corticosteroids) is common, but minimizing immunosuppression safely is the goal.

Identifying who can benefit involves complex considerations, including genetic and immunologic profiling.

Achieving a balance is crucial to prevent rejection while minimizing infection and malignancy risks. Researchers seek personalized approaches to improve outcomes for KTRs.

Role of IFX induction in transplantation

Infliximab (IFX) is a chimeric mouse–human monoclonal antibody that inhibits tumor necrosis factor-alpha (TNF-α), which is approved for use in inflammatory autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease.

Previous studies suggest that TNF-α inhibition in transplantation may decrease tissue injury, and IFX selectively binds to transmembrane TNF-α that dampens recently activated immune effector cells involved in antigraft activity around the time of organ transplantation.

There is growing interest in the role of IFX induction in transplantation. The Clinical Trials in Organ Transplantation-19 (CTOT-19) study is currently the largest randomized, double-blind, placebo-controlled, multicenter phase II study investigating the effect of IFX as induction therapy in 225 deceased donor KTRs.

The goal of IFX was to abrogate ischemia–reperfusion injury that might impact graft function and not to minimize immunosuppression. It found no significant between-group differences in the primary outcome of estimated glomerular filtration rate (eGFR) at 24 mo.

Furthermore, rates of delayed graft function, biopsy-proven acute rejection (BPAR), emergence of de novo donor-specific antibodies (dnDSAs), and graft loss or death were similar.

It demonstrated significantly higher rates of BK viremia (29% versus 13%, P = 0.004) and more BK nephropathy (13 versus 5%, P = 0.006).

Notably, participants in CTOT-19 received rabbit antithymocyte globulin (4.5–6 mg/kg) along with a single dose of IFX (3 mg/kg), maintained on tac/MMF/steroid. These results question the utility of IFX as induction.

In this issue of Transplantation, the RIMINI investigators further our knowledge of IFX by hypothesizing that induction with rabbit antithymocyte globulin (3 mg/kg) followed by IFX (5 mg/kg) can safely allow a 2-drug regimen of tac/steroids with MMF avoidance.

It was a prospective, single-arm, open-label, international multicenter study following 67 primary KTRs with calculated panel reactive antibody <20% and absent dnDSAs at randomization.

The primary endpoint is defined as “efficacy failure” (composite of BPAR, graft loss, or poor graft function defined as eGFR <40 mL/min/1.73 m2 at 12 mo).

Efficacy failure was chosen to match the endpoint of the OSAKA trial, an open-label, parallel-group study that randomized adult KTRs to daily versus twice-daily tacrolimus.

In RIMINI, 32.8% of patients met primary endpoint, which was identical to a historical cohort drawn from patients transplanted at the same participating centers and matched for deceased/living donor, donor age, recipient age and sex, and cytomegalovirus serostatus.

In contrast to CTOT-19, the current study found lower rates of BK viremia or nephropathy (6% IFX versus 22% control, P = 0.013) but higher rates of dnDSAs (12% IFX versus 1.5% control, P = 0.039).

Immunologically, rates of BPAR were 16.4% in RIMINI participants compared with ~10% in those on a tac/MMF/steroid standard regimen in CTOT-19.

By comparison, the rate of BPAR in the matched cohort was 22%, but it is unclear what or if any induction or which maintenance immunosuppressants were historically used.

Also, BPAR rates in OSAKA involving similar study participants ranged 10% to 16% across European centers deploying a tac/MMF/steroid regimen.

Although the Banff grading of acute rejections was not reported, it is worrisome that of the 11 patients with BPARs seen in RIMINI, 1 resulted in graft loss, whereas 5 others eventually suffered poor graft function, arguing against these being low-grade rejections readily amenable to treatment.

Ten of 13 episodes of acute rejection were clinically manifest (ie, associated allograft dysfunction) and found on indication biopsies. Aside from acute rejections, there were 3 cases of chronic rejections not accounted for by the primary endpoint.

Although its inclusion would not have swayed the final results, it still reflects the elevated immunologic risk with an MMF-avoidance protocol. It is unclear whether the historical cohort were subject to routine dnDSAs testing analogous to the study; therefore, at least a partial explanation for the higher rates of dnDSAs among RIMINI participants could be due to increased surveillance. Reassuringly, renal allograft function was similar in the RIMINI study as measured by eGFR at 12 mo compared with that in OSAKA (6 mo) and CTOT-19 (24 mo).

Rates of delayed graft function (27%) and primary nonfunction (3%) in RIMINI were not significantly different from most published rates.

Kidney Donor Profile Index scores were not reported in the RIMINI study; similar allograft function argues against significant organ quality differences between studies.

Rates of serious adverse other than BKV infections were similar to the historical cohort. As always, there are several limitations to the generalizability of the study.

Most participants were of White race, of low immunologic risk, and first-time KTRs. These may not be translatable to a more ethnically diverse population or those receiving subsequent transplants with greater HLA sensitization.


Taken together, the higher than customary rates of BPAR in RIMINI along with lower rates of BK infections, signal gross underimmunosuppression in those on MMF-avoidance maintenance therapy.

Even more worrisome is the emergence of dnDSAs among subjects, a harbinger of antibody-mediated rejections that may be associated with poorer overall allograft function.

Prior attempts at MMF withdrawal have shown higher rejection rates and inferior allograft outcomes, mirroring results from calcineurin withdrawal studies even among low immunologic risk individuals.

Unfortunately, immunosuppression minimization/avoidance remains elusive, whether with antimetabolites or calcineurin inhibitors.

The transplant community has yet to wean itself off the canonical triple regimen of tac/MMF/steroid, at least for now, without jeopardizing allograft outcomes.


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